In 2003, the adjusted mean CD4 at enrollment was 79.3 cells per cubic millimeter (45.0, 113.6) greater in MSM than in heterosexual risk, 70.8 cells per cubic millimeter (10.7, 130.9) greater in IDU than in heterosexual risk, and not significantly different between MSM and IDU. In 2011, the adjusted mean CD4 at enrollment was 45.2 cells per cubic millimeter (12.7, 77.7) greater in MSM than in heterosexual risk and not significantly different between either MSM and IDU or IDU and heterosexual risk.
MSM and heterosexual risk groups had an increase in the slope of CD4 at enrollment per year over the interval 2008–2011 (Table 4). There was no increase in the slopes of CD4 at enrollment per year among IDU and other HIV risk categories over the interval 2008–2011 (Table 4).
For those aged >30 years, age categories did not differ in adjusted mean CD4 at enrollment in 2003. In 2003, subjects aged ≤30 years had an adjusted CD4 at enrollment greater than subjects in age categories 31–40 years [69.1 cells per cubic millimeter (30.4, 107.8)], 41–50 years [82.5 cells per cubic millimeter (40.7, 124.2)], and >50 years [72.5 cells per cubic millimeter (−13.8, 158.9)—not significant]. In 2011, the adjusted mean enrollment CD4 was 63.4 cells per cubic millimeter (17.5, 109.3) greater in 31–40 years than in >50 years, but not significantly different between either 31–40 and 41–50 years or 41–50 and >50 years. However, the adjusted 2011 mean enrollment CD4 in subjects ≤30 years was greater than in subjects in age categories 31–40 years [52.1 cells per cubic millimeter (16.0, 88.3)], 41–50 years [79.9 cells per cubic millimeter (41.8, 117.9)], and >50 years [115.5 cells per cubic millimeter (72.2, 158.8)].
CD4 at enrollment increased per year over the interval 2008–2011 for age categories ≤30, 31–40, 41–50 years, but not for >50 years (Fig. 2 and Table 4). Compared with age category >50 years, the CD4 at enrollment slope over the interval 2008–2011 was greater in age categories ≤30 years (13.4 cells per cubic millimeter per year [0.9–25.9]) and 31–40 years [17.8 cells per cubic millimeter per year (5.1–30.5)].
This study demonstrates an increase in CD4 at enrollment of 11.2 cells per cubic millimeter per year among new presenters at HIVRN sites over the interval 2008–2011 after adjusting for demographic factors and clinic site. In contrast, there was no change in CD4 count at enrollment during 2003–2007. Our data suggest that although time to presentation to care and degree of immunosuppression at presentation have been decreasing among persons living with HIV since 2008, the rate of decrease is very slow. Finally, as in previous studies, we demonstrate that there continue to be disparities in enrollment CD4 among those presenting to HIV care, with lower CD4 counts among Hispanics and blacks compared with among whites, heterosexual risk compared with MSM, and age >30 years compared with age ≤30 years.
The observed increase in CD4 at enrollment per year has several implications. We observed that the proportion CD4 ≥350 cells per cubic millimeter increased by 1.45% per year after 2008. This increase represents >500 patients per year linked to care with a CD4 ≥350 cells per cubic millimeter, to the extent that these data can be extrapolated to the national level (assuming 48,000 HIV diagnoses per year in the United States17 and 77% linkage to care8). Although encouraging, this likely represents <3% of late presenters in the United States, assuming 54% late presentation percentage.10,18
Our findings suggest that the time to presentation, as assessed by enrollment CD4, is declining slowly, and further interventions for HIV testing and linkage to care are needed. Diagnosis and linkage to care are necessary for HIV-infected patients to present for care.8,9 Recently, the US Preventative Services Task Force released a statement recommending screening of all patients aged between 15 and 64 years or patients of any age with HIV risk factors.19 Further, in July 2012, the Food and Drug Administration approved the first over-the-counter oral rapid HIV test. These new recommendations and testing technologies may increase screening rates and further decrease the time to presentation.
A recent systematic review found no meaningful increase in CD4 at presentation in developed countries from 1992 to 2011.20 The metaregression used in this analysis only examined CD4 as a continuous linear trend over the study period and did not allow the slope to vary after 2007 as in our analysis and was limited by sparse data over 2010 and 2011. Further, this analysis was unable to adjust for demographic factors. For these reasons, we believe our model better represents the current trends in CD4 at presentation in the United States.
Whites had a higher CD4 at enrollment than did blacks or Hispanics from 2003 to 2011; however, we did observe an increase in CD4 at enrollment for both blacks and Hispanics. Nevertheless, there is a cause for concern in both these racial/ethnic groups. It has long been recognized that blacks carry the largest burden of HIV infection in the United States.17 More recently, a CDC study found that rates of new HIV diagnoses in Hispanics were 2.8-fold higher than in whites in 2010.21 Given that the burden of new HIV diagnoses is in blacks and Hispanics and the slow rate of increase in CD4 count at enrollment, additional targeted efforts focusing on decreasing time to presentation to care are needed in these racial/ethnic groups.
According to our model, MSM had a higher CD4 at enrollment than did subjects with heterosexual risk in all years. This may be due to increased awareness of HIV risk among MSM resulting in increased patient-initiated screening. MSM may also encounter health care more frequently and have increased provider-initiated HIV screening. In contrast to MSM and heterosexual risk, IDU failed to increase mean CD4 at enrollment between 2008 and 2011. In part, this may be driven by low numbers of IDU participants in our study. However, it is also plausible that improvements in screening and linkage to care in MSM and heterosexual risk would not necessarily have a similar impact in IDU.
Consistent with the findings of a prior study that showed subjects ≤35 years old were less likely to present late,11 we found that adult subjects ≤30 years had a higher enrollment CD4 than did those subjects >30 years. Further, we showed that subjects >50 years old did not have any improvement in enrollment CD4 over time, whereas in all other age categories, there was an increase during 2008–2011 (Table 4). It is known that CD4 decreases with age in HIV-seronegative individuals,22 and that older individuals have a lower CD4 after seroconversion.23 To what degree these age-related CD4 effects contribute to the observed disparity is not known. Nevertheless, age-related changes in CD4 should not have affected the annual increase in enrollment CD4 and suggest that there was no decrease in time to presentation to care in patients >50 years between 2008 and 2011. Additional studies to confirm this finding and develop interventions are needed.
This study has several limitations. We sought to determine if time to presentation was decreasing over time and, in particular, after the CDC guideline revision in September 2006; however, it should be noted that there are many other possible explanations for the increasing CD4 at presentation for HIV care after 2008. The changes to the HIV screening guidelines are well documented and occur at the national level, but changes in other aspects of screening such as increased awareness about HIV and improved access to testing may be heterogeneous and represent potential contributing factors that were not directly assessed. HIV-screening practices may have also changed by race/ethnicity over the study period. During 2007–2010, the CDC launched the Expanded Testing Initiative,24 which was focused on increasing HIV testing among blacks and Hispanics. We have no information about participation in the Expanded Testing Initiative by any of our participating sites. Introduction of rapid HIV testing also occurred during the study period, which may have heterogeneously affected local screening practices. This study was not able to directly assess the effect of the many changes in HIV screening that have occurred during the study period.
Similarly, we had no means of assessing time to linkage to care within our cohort, but this can clearly affect time from HIV infection to presentation to care as well. Future studies should assess changes in linkage to HIV care. CD4 is not a perfect surrogate for time to presentation. At the population level, we know that CD4 decline is roughly linear over time,25 but there is a wide individual variation and even variation among race/ethnicity.26–28 However, there is currently no better method for retrospectively assessing time from HIV infection to presentation to care. It is possible that a small portion of our newly presenting subjects had received HIV care before enrollment. We took measures to exclude such patients from analyses; however, we do not have comprehensive access to all outside medical records preceding enrollment. Finally, the HIVRN population is selected from patients who primarily present to urban academic HIV specialty clinics, which limits generalizability.
In summary, we have demonstrated a small, but statistically significant, increase in the CD4 count at enrollment in new presenters to primary HIV care after the revision of the CDC HIV testing guidelines. This increase is encouraging, but many patients continue to present late, and the current rate of increase is slow. Additionally, our study suggests that racial/ethnic, HIV risk factor, and age-related disparities exist in time to presentation to HIV care. Further population-specific efforts are needed to decrease the time from HIV infection to presentation to care.
Participating sites: Alameda County Medical Center, Oakland, CA (Howard Edelstein, MD); Children's Hospital of Philadelphia, Philadelphia, PA (Richard Rutstein, MD); Community Health Network, Rochester, NY (Roberto Corales, DO); Drexel University, Philadelphia, PA (Jeffrey Jacobson, MD, Sara Allen, CRNP); Fenway Health, Boston, MA (Stephen Boswell, MD); Johns Hopkins University, Baltimore, MD (Kelly Gebo, MD, Richard Moore, MD, Allison Agwu, MD); Montefiore Medical Group, Bronx, NY (Robert Beil, MD, Carolyn Chu, MD); Montefiore Medical Center, Bronx, NY (Lawrence Hanau, MD); Oregon Health and Science University, Portland, OR (P. Todd Korthuis, MD); Parkland Health and Hospital System, Dallas, TX (Muhammad Akbar, MD, Laura Armas-Kolostroubis, MD); St Jude's Children's Hospital and University of Tennessee, Memphis, TN (Aditya Gaur, MD); St Luke's Roosevelt Hospital Center, NY, New York (Victoria Sharp, MD, Stephen Arpadi, MD); Tampa General Health Care, Tampa, FL (Charurut Somboonwit, MD); University of California, San Diego, CA (W. Christopher Mathews, MD); Wayne State University, Detroit, MI (Jonathan Cohn, MD). The authors would like to thank Cindy Voss for the management, cleaning, and quality assurance of the data used in this manuscript.
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Keywords:© 2014 by Lippincott Williams & Wilkins
HIV; CD4 count; presentation to care; linkage to care; HIV screening